Multiple Mechanisms for Pain - How Can We Improve the Chances of Success?

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1 Multiple Mechanisms for Pain - How Can We Improve the Chances of Success? Ann Hayes October 2017

2 What are the different types of pain? Neuropathic Diabetic neuropathy, PHN, sciatica Caused by damage to neurones Involves central and peripheral sensitization Inflammatory Arthritis, trauma, back pain Caused by tissue damage and release of inflammatory mediators Involves central and peripheral sensitization Nociceptive Caused by potentially tissue damaging stimuli Defensive role Involves transmission along pain pathway Functional/Visceral Fibromyalgia, IBS, migraine May be caused by visceral stimulation; cause often unknown Mixed pathophysiology

3 What drugs are used to treat pain in the clinic? Inflammatory Pain Paracetamol NSAIDs ibuprofen, diclofenac, naproxen Opioids morphine, oxycodone, codeine Combinations Neuropathic Pain Gabapentinoids gabapentin, pregabalin Monoamine reuptake inhibitors amitriptyline, duloxetine Opioids Local anaesthetics lidocaine patch Generally old drugs Efficacy? Opioids less effective vs neuropathic pain NSAIDs low ceiling Neuropathic pain drugs only effective in 30 50% of patients Side effects Opioids: respiratory depression, dependence, constipation NSAIDs: GI and CV effects Gabapentinoids: sedation

4 Huge effort to find new drugs! 3006 Ph II/III trials found in clinicaltrials.gov searching on pain and drug in July 2017 Successes COX2 inhibitors New gabapentinoids, pregabalin Ziconotide for intractable pain Noradrenaline uptake inhibitors for fibromyalgia and neuropathic pain Triptans for migraine Failures Fatty Acid Amide Hydrolase (FAAH) inhibitors Trpv1 antagonists Purinergic P2X7 antagonists Cannabinoid CB2 agonists Glial cell modulators Neurokinin NK1 antagonists Adenosine A1 agonists C-C chemokine receptor type 2 (CCR2) antagonists α4β2 nicotinic receptor agonists NMDA glycine site inhibitors

5 What can we learn from successes and failures to increase our chances of success?

6 Use clinically validated mechanisms? Successes COX2 inhibitors New gabapentinoids, pregabalin Ziconotide for intractable pain Noradrenaline uptake inhibitors for fibromyalgia and neuropathic pain Triptans for migraine Failures (lack of efficacy) Fatty Acid Amide Hydrolase (FAAH) inhibitors Trpv1 antagonists Purinergic P2X7 antagonists Cannabinoid CB2 agonists Glial cell modulators Neurokinin NK1 antagonists Adenosine A1 agonists C-C chemokine receptor type 2 (CCR2) antagonists α4β2 nicotinic receptor agonists NMDA glycine site inhibitors

7 Inhibitors of voltage-gated calcium channels Gabapentin Originally launched for epilepsy Trialled in neuropathic pain because of precedented use of anticonvulsants like carbamazepine Mechanism subsequently identified as inhibition of α2δ calcium channel subunits And inhibition of neurotransmitter release eg glutamate Pregabalin Ziconotide

8 Ziconotide N-type calcium channel inhibitor Synthetic form of ω- conotoxin peptide, derived from cone snail N-type calcium channel inhibitor; binds to pore and occludes channel Ziconotide Gabapentin Effective in severe, intractable pain Has to be given intrathecally (CV effects) Poor T.I. CNS effects Rauck et al, J Pain Symptom Manage. 2006;31(5):

9 Use-dependent Inhibitors of N-type calcium channels e.g. CNV (Calchan/Biogen) State-dependent channel blocker Well tolerated in ph I Inactive in 2 Ph II studies; on company website says company is considering alternative dosing regimes Other state-dependent blocker, Z160 (Zalicus) also inactive in the clinic WHY? Wrong target Wrong clinical population? (lumbosacral radiculopathy, diabetic neuropathy, post herpetic neuralgia) Insufficient target engagement? Patel et al, Br. J. Pharmacol., 2017, Mar 20. doi: /bph.13789

10 Inhibitors of voltage-gated sodium channels Local anaesthetics (eg lidocaine patch for post-herpetic neuropathy) Anticonvulsants (eg carbamazepine for trigeminal neuralgia) Use dependent blockers Effective but poor side-effect profile after systemic/oral administration Non-selective

11 Voltage-gated sodium channels Channel (Nav) Location Pathophysiology Desired activity 1.1 CNS, heart Epilepsy 1.2 CNS, peripheral neurones Epilepsy 1.3 CNS, peripheral neurones, Epilepsy, pain? heart 1.4 Skeletal muscle X 1.5 Heart, GI tract Cardiac function X 1.6 CNS, DRG, heart, glia Epilepsy 1.7 Sensory afferents Pain 1.8 Sensory afferents Pain 1.9 Sensory afferents Pain

12 What can we learn from successes and failures to increase our chances of success? Use mechanisms validated by human genetics?

13 Nav1.7 gene mutations and pain Gain of function mutations Loss of function mutations Erythromelalgia Burning pain of feet, lower legs and hands Increased channel activity Other mutations cause paroxysmal extreme pain disorder, due to impaired channel inactivation Congenital insensitivity to pain Patients have injuries to mouth, cuts/bruises and unnoticed fractures Impaired firing of action potentials in DRG

14 Clinical effects of Nav1.7 blockers Compound Selectivity State dependence Vixotrigine/ CNV Biogen Funapide (XEN402/TV 45070), Teva PF X vs Nav1.5 Lower selectivity vs other Navs (1) Nav1.7 &Nav1.8 Nav1.7 selective State dependent State dependent State dependent CNS penetration Clinical activity Yes Positive efficacy in trigeminal neuralgia and sciatica; well tolerated (2)?? +ve effect in 4 erythromelalgia patients after oral admin (3) No effect on primary endpoint in PHN after topical admin; but did show increased responders vs placebo (2)?? No effect in erythromelalgia or dental pain; well tolerated 1 Zakrzewska et al, Trials. 2013; 14: GlobalData database, July Goldberg et al, Pain. 2012, 153:80 5

15 Where to go with sodium channel blockers? Activity against channels other than Nav1.7 may be useful eg 1.8, 1.9, even central channels like 1.2 and 1.3 Nav 1.8 muta ons painful neuropathy (Faber et al, 2012) Nav 1.9 muta ons pain syndromes (Zhang et al, 2013; Huang et al, 2014)

16 Hereditary sensory and autonomic neuropathy (HSAN) Genetic disorder characterised by loss of pain sensation Caused by mutations in either nerve growth factor (NGF) or its receptor, Trk A NGF sensitises nociceptors in a variety of ways

17 NGF antibodies are analgesic in the clinic Tanezumab (Pfizer) Fasinumab (Regeneron) Fulranumab (Amgen/JNJ) Osteoarthritis Chronic low back pain Diabetic neuropathy Cystitis FDA clinical hold in 2010 due to osteonecrosis & increased hip replacements; lifted 2012 Cancer pain Tanezumab, Ph III Fasinumab, Ph III Fulranumab,??

18 June 13, :00 AM Eastern Daylight Time NEW YORK & INDIANAPOLIS - Pfizer Inc. (NYSE:PFE) and Eli Lilly and Company (NYSE:LLY) today announced that the U.S. Food and Drug Administration (FDA) has granted Fast Track designation for tanezumab for the treatment of chronic pain in patients with osteoarthritis (OA) and chronic low back pain (CLBP). Tanezumab is an investigational humanized monoclonal antibody that selectively targets, binds to and inhibits nerve growth factor (NGF). It is the first NGF inhibitor to receive Fast Track designation, a process designed to facilitate the development and expedite the review of new therapies to treat serious conditions and fill unmet medical needs.

19 Effect of NGF antibody tanezumab in PhIII trial in osteoarthritis pain (WOMAC pain subscale) Brown et al, Arthritis Rheum., 2013, 65:

20 What can we learn from failures? Fatty Acid Amide Hydrolase (FAAH) inhibitors Trpv1 antagonists Purinergic P2X7 antagonists Cannabinoid CB2 agonists Glial cell modulators Neurokinin NK1 antagonists Adenosine A1 agonists C-C chemokine receptor type 2 (CCR2) antagonists α4β2 nicotinic receptor agonists NMDA glycine site inhibitors

21 Was target engagement demonstrated in man at site of action? Compound Target Engage ment Method FAAH inhibitors Enzyme inhibition Trpv1 antagonists Increased heat pain threshold P2X7 antagonists X CB2 agonists Glial cell modulators NK1 antagonists PET A1 agonists X X X CCR2 antagonists Inhibition of ligand CCL2 α4β2 agonists X Without demonstration of target engagement, don t know if molecule or mechanism has failed NMDA glycine inhibs X

22 Single target/mechanism selectivity? Fatty Acid Amide Hydrolase (FAAH) inhibitors Trpv1 antagonists Purinergic P2X7 antagonists Cannabinoid CB2 agonists Glial cell modulators Neurokinin NK1 antagonists Adenosine A1 agonists C-C chemokine receptor type 2 (CCR2) antagonists α4β2 nicotinic receptor agonists NMDA glycine site inhibitors Need to target key control pathways Or final common pathway

23 Issues with animal models Choose a specialist (CRO or academic lab) that routinely does pain testing Have the studies replicated in an independent lab Check blinding and randomisation procedures Is an appropriate positive control being used, at an appropriate dose? Add a negative control? Animals should only be excluded to pre stated criteria Use a range of models if possible and a range of endpoints across all sensory modalities Try to incorporate endpoints that reflect ongoing pain (eg weight bearing) and emotional aspects (eg conditioned place preference) Need to test compounds therapeutically rather than prophylactically ie after development of pain

24 Issues with pain clinical trials.. Subjective endpoints Heterogeneous patient populations (diagnosis and pathophysiology) Placebo response rates CGRP antagonist olcegepant in acute migraine NGF antibody in OA

25 Conclusions If possible pick a mechanism with some clinical validation Key approach is better selectivity eg COX2, but if single target needs to be on key control or convergent point in pathway Knowledge from genetic mutations has been helpful Target engagement at the site of action, in man, should be demonstrated In the clinic, choice of an appropriate clinical model or population may increase probability of success